EP1223929B1 - Derives indoliques cannabimimetiques - Google Patents

Derives indoliques cannabimimetiques Download PDF

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Publication number
EP1223929B1
EP1223929B1 EP00972266A EP00972266A EP1223929B1 EP 1223929 B1 EP1223929 B1 EP 1223929B1 EP 00972266 A EP00972266 A EP 00972266A EP 00972266 A EP00972266 A EP 00972266A EP 1223929 B1 EP1223929 B1 EP 1223929B1
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Prior art keywords
compound
group
cannabinoid
indole
receptor
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EP1223929A4 (fr
EP1223929A1 (fr
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Alexandros Makriyannis
Hongfeng Deng
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University of Connecticut
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University of Connecticut
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention relates generally to cannabinoid analogs and is more particularly concerned with new and improved indole cannabinoid analogs exhibiting high binding affinities for cannabinoid receptors, pharmaceutical preparations employing these analogs and these analogs for use in providing a physiological effect.
  • Classical cannabinoids such as the marijuana derived cannabinoid ⁇ 9 -tetrahydrocannabinol, ( ⁇ 9 -THC) produce their pharmacological effects via interaction with specific cannabinoid receptors in the body.
  • CB1 a central receptor found in the mammalian brain and peripheral tissues
  • CB2 a peripheral receptor found only in the peripheral tissues.
  • Compounds that are agonists or antagonists for one or both of these receptors have been shown to provide a variety of pharmacological effects. See, for example, Pertwee, R.G., Pharmacology of cannabinoid CB1 and CB2 receptors, Pharmacol.
  • cannabinoid analogs possessing high affinity for one of the CB1 or CB2 receptors and/or metabolic stability. Such analogs may offer a rational therapeutic approach to a variety of disease states.
  • One class of cannabimimetic analogs encompasses indole derivatives such as the well known aminoalkylindoles represented by WIN 55212-2 ⁇ (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo[1,2,3- de ]-1,4-benzoxazin-6-yl](1-naptha-lenyl)methanone ⁇ .
  • Aminoalkylindoles of this type typically have a carbon linked alkylheterocyclic substituent at the indole-1 position, which is believed to be important for their canabimimetic activities. These known materials are not selective for preferential activation of one of the CB1 or CB2 receptors.
  • Aminoalkylindoles have been found to act as agonists for the CB1 and CB2 receptors and occasionally as antagonists for the CB1 and CB2 receptors.
  • the invention includes compounds selective for the CB2 receptors. Further, some of the compounds have agonistic or antagonistic properties.
  • One aspect of the invention includes novel cannabinoid analogs of the formula: including any optical isomers thereof, and physiologically acceptable salts thereof wherein,
  • the analogs of this embodiment show high binding affinities for the CB1 and CB2 cannabinoid receptors. More importantly, some of these compounds show not only comparable cannabimimetic activity with the compound WIN 55212-2 but also a surprisingly higher selectivity for the CB2 receptors. More specifically, the inventive analogs showed similar or higher receptor binding affinity than the well-known indole cannabinoid WIN 55212-2.
  • CB2 selective cannabinoids are able to activate the CB2 receptor and thereby modulate the immune system with little psychoactivity or other CNS effects, these analogs are possible therapeutic agents. Additionally, some of the iodide and fluoride containing analogs are potential radioactive probes for imaging in vivo the distribution of cannabinoid receptors. The azido modified analogs are excellent affinity probes for characterizing binding pockets of cannabinoid receptors.
  • the novel cannabimimetic indole derivatives described herein, and physiologically acceptable salts thereof represent potentially useful materials for providing a physiological effect to treat pain, peripheral pain, glaucoma, epilepsy, nausea such as associated with cancer chemotherapy, AIDS Wasting Syndrome, cancer, neurodegenerative diseases including Multiple Sclerosis, Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, mental disorders such as Schizophrenia and depression; to prevent or reduce endotoxic shock and hypotensive shock; to modulate appetite; to reduce fertility; to prevent or reduce diseases associated with motor function such as Tourette's syndrome; to prevent or reduce inflammation; to provide neuroprotection and to effect memory enhancement.
  • novel cannabimimetic indole derivatives described herein also provide useful materials for testing the cannabinoid system.
  • another aspect of the invention is the use of an inventive compound, or a physiologically acceptable salt thereof, to provide a physiological effect in an individual or animal.
  • a "therapeutically effective amount" of a compound is the quantity of a compound which, when administered to an individual or animal, results in a sufficiently high level of that compound in the individual or animal to cause a discernible increase or decrease in stimulation of cannabinoid receptors.
  • Physiological effects that result from cannabinoid receptor stimulation include analgesia, decreased nausea resulting from chemotherapy, sedation and increased appetite.
  • Other physiological functions include relieving intraocular pressure in glaucoma patients and suppression of the immune system.
  • about 10 mg/day to about 1,000 mg/day is a possible "therapeutically effective amount" for the inventive compounds.
  • an "individual” refers to a human.
  • An “animal” refers to, for example, veterinary animals, such as dogs, cats or horses and farm animals, such as cows or pigs.
  • the compound of the present invention can be administered by a variety of known methods, including orally, rectally, or by parenteral routes (e.g., intramuscular, intravenous, subcutaneous, nasal or topical).
  • parenteral routes e.g., intramuscular, intravenous, subcutaneous, nasal or topical.
  • the form in which the compounds are administered will be determined by the route of administration.
  • Such forms include, but are not limited to, capsular and tablet formulations (for oral and rectal administration), liquid formulations (for oral, intravenous, intramuscular or subcutaneous administration) and slow releasing microcarriers (for rectal, intramuscular or intravenous administration).
  • the formulations can also contain a physiologically acceptable vehicle and optional adjuvants, flavorings, colorants and preservatives.
  • Suitable physiologically acceptable vehicles may include, for example, saline, sterile water, Ringer's solution, and isotonic sodium chloride solutions.
  • the specific dosage level of active ingredient will depend upon a number of factors, including, for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual being treated.
  • the inventive cannabinoid analogs are generally described by the structural formula previously disclosed.
  • the following examples are given for purposes of illustration only in order that the present invention may be more fully understood. These examples are not intended to limit in any way the practice of the invention.
  • the prepared cannabimimetic indole derivatives can generally be described with reference to structural formula 1 below and include physiologically acceptable salts thereof.
  • the inventive cannabimimetic indole derivatives of structural formula 1 include both racemics and two enantiomers.
  • TABLE 1 The inventive materials of structural formula 1 are listed in TABLE 1. It should be noted that R 1 -X for all of the materials of TABLE 1 was 1-(N-Methyl-2-piperidinyl)methyl. All of the materials of TABLE 1 have a chiral center and the binding affinities of the materials of TABLE 1 were obtained by evaluating their racemic samples. TABLE 1 K I nM analog Z R 2 R 3 CB1 CB2 AM22O9 N 3 H 5-azido-2-iodophenyl 48.8 41.8 AM2223 NCS H 5-isothiocyanato-2-iodophenyl 64.8 29.9
  • binding affinity is represented by the IC 50 value which is the concentration of an analog required to occupy the 50% of the total number (Bmax) of the receptors. The lower the IC 50 value the higher the binding affinity.
  • an analog is said to have "binding selectivity” if it has higher binding affinity for one receptor compared to the other receptor; e.g. a cannabinoid analog which has an IC 50 of 0.1 nM for CB1 and 10 nM for CB2, is 100 times more selective for the CB1 receptor.
  • the binding affinities (K i ) are expressed in nanomoles (nM) and are listed in TABLE 1 above.
  • TME Tris-HCl buffer, 5 mM MgCl 2 and 1 mM EDTA
  • the treated membranes were subsequently used in the binding assay described below. Approximately 30 ⁇ g of membranes were incubated in silanized 96-well microtiter plate with TME containing 0.1 % essentially fatty acid-free bovine serum albumin (BSA), 0.8 nM [ 3 H] CP-55,940, and various concentrations of test materials at 200 °C for 1 hour. The samples were filtered using Packard Filtermate 196 and Whatman GF/C filterplates and washed with wash buffer (TME) containing 0.5% BSA. Radioactivity was detected using MicroScint 20 scintillation cocktail added directly to the dried filterplates, and the filterplates were counted using a Packard Instruments Top-Count.
  • BSA bovine serum albumin
  • Nonspecific binding was assessed using 100 nM CP-55,940. Data collected from three independent experiments performed with duplicate determinations was normalized between 100% and 0% specific binding for [ 3 H] CP-55,940, determined using buffer and 100 nM CP-55,940. The normalized data was analyzed using a 4-parameter nonlinear logistic equation to yield IC 50 values. Data from at least two independent experiments performed in duplicate was used to calculate IC 50 values which were converted to K i values using the assumptions of Cheng et al, Relationship Between the Inhibition Constant (K i ) and the concentration of Inhibitor which causes 50% Inhibition (IC 50 ) of an Enzymatic Reaction, Biochem. Pharmacol., 22, 3099-3102, (1973).
  • Muller-Vahl KB Schneider U, Kolbe H, Emrich, HM. Treatment of Tourette's syndrome with delta-9-tetrahydrocannabinol . Am. J. Psychiat. (1999) 156-195. Muller-Vahl KB, Kolbe H, Schneider U, Emrich, HM Cannabis in movement disorders . Porsch. Kompicmentarmed (1999) 6 (suppl. 3) 23-27. Consroe P, Musty R, Rein J, Tillery W, Pertwee R. The perceived effects of smoked cannabis on patents with multiple sclerosis, Eur. Neurol. (1997) 38-44-48. Pinnegan-Ling D, Musty R.
  • Marinol and phantom limb pain a case study. Proc Inv. Cannabinoid Rea. Sec. (1994):53. Brenneisen R, Pgli A, Elsohly MA, Henn V. Spiess Y: The effect of orally and rectally administered ⁇ 9- tetrahydrocannabinol on spasticity, a pilot study with 2 patients. Int. J. Clin Pharmacol Ther. (1996) 34:446-452. Martyn CN. Illis LS, Thom J. Nabilone in the treatment of multiple sclerosis. Lancet (1995) 345:579 . Maurer M, Henn V, Dittrich A, Hofmann A.
  • Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial.
  • Richardson JD Kilo S. Hargreaves KM
  • Cannabinoids reduce dryperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain (1998) 75:111-119.
  • AM2209 and AM2223 show a selectivity for the CB2 receptor.
  • inventive analogs described herein, and physiologically acceptable salts thereof have high potential when administered in therapeutically effective amounts for providing a physiological effect useful to treat pain, peripheral pain, glaucoma, epilepsy, nausea such as associated with cancer chemotherapy, AIDS Wasting Syndrome, cancer, neurodegenerative diseases including Multiple Sclerosis, Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, mental disorders such as Schizophrenia and depression; to prevent or reduce endotoxic shock and hypotensive shock; to modulate appetite; to reduce fertility; to prevent or reduce diseases associated with motor function such as Tourette's syndrome; to prevent or reduce inflammation; to provide neuroprotection and to effect memory enhancement.
  • another aspect of the invention is the administration of a therapeutically effective amount of an inventive compound, or a physiologically acceptable salt thereof, to an individual or animal to provide a physiological effect.
  • iodide and fluoride containing compounds are potential radioactive probes which would be useful for imaging in vivo the distribution of cannabinoid receptors.
  • azido containing compounds would be useful as affinity probes for characterizing binding pockets of cannabinoid receptors.

Abstract

L'invention concerne de nouveaux dérivés indoliques cannabimimétiques présentant une affinité privilégiée pour un des sites récepteurs cannabinoïdes CB1 ou CB2. Cette plus grande affinité pour ce récepteur rend ces analogues très utiles d'un point de vue thérapeutique comme médicaments administrés à des individus et à des animaux dans le traitement de la douleur, du glaucome, de l'épilepsie, et de la nausée associée à la chimiothérapie.

Claims (10)

  1. Composé de formule générale :
    Figure imgb0009
     comprenant l'un quelconque des isomères optiques de celui-ci, et les sels pharmaceutiquement acceptables de celui-ci, dans lequel :
    Z peut être dans la position 4-, 5-, 6- ou 7- et est choisi parmi le groupe constitué par un nitro, un atome d'hydrogène (H), un groupe halogène, un nitroso, un amino, un alkylamino en C1-C7, un dialkylamino en C1-C7, un azido, un cyano, un isothiocyano et un phényle ;
    X est choisi parmi le groupe constitué par un groupe halogène, un atome d'hydrogène, un méthyle, un hydroxy, un alcanoate en C1-C7, un formyle, un amino, un cyano, un isothiocyano et un azido ;
    R1 est le 2-,3- ou 4-pipéridinyle interconnecté à la position indole-1 avec un ou deux atomes de carbone ;
    R2 est choisi parmi le groupe constitué par un atome d'hydrogène (H) et un groupe alkyle en C1-C7;
    Y est choisi parmi le groupe constitué par un carbonyle et un CH=CH (cis ou trans) ; et
    R3 est un phényle substitué par deux substituants à partir du groupe constitué par un groupe halogène, un nitro, un nitroso, un amino, un alkylamino en C1-C7, un dialkylamino en C1-C7, un hydroxy, un méthoxy, un groupe alkyle en C1-C7, un azido, un cyano et un isothiocyano.
  2. Composé selon la revendication 1, dans lequel Z est en position indole-6 et est choisi parmi le groupe constitué par un atome d'hydrogène (H), un NO2, un NH2 et un groupe halogène.
  3. Composé selon la revendication 1, dans lequel Y est un C=O.
  4. Composé selon la revendication 1, dans lequel R2 est choisi parmi le groupe constitué par un atome d'hydrogène (H) et un CH3.
  5. Composé selon la revendication 1, dans lequel Z est dans la position 4-, 5- ou 7-.
  6. Composé selon la revendication 1, dans lequel R1 est le 2-pipéridinyle interconnecté à la position indole-1 avec un ou deux atomes de carbone.
  7. Composé selon la revendication 6, dans lequel R1 est le (2-pipéridinyl)méthyle.
  8. Préparation pharmaceutique comprenant un véhicule pharmaceutiquement acceptable et le composé selon l'une quelconque des revendications 1 à 7.
  9. Composé selon l'une quelconque des revendications 1 à 7, pour une utilisation en thérapie.
  10. Composé selon l'une quelconque des revendications 1 à 7, pour une utilisation dans la stimulation d'un récepteur de cannabinoide chez un individu ou un animal.
EP00972266A 1999-10-18 2000-10-18 Derives indoliques cannabimimetiques Expired - Lifetime EP1223929B1 (fr)

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US15999799P 1999-10-18 1999-10-18
US159997P 1999-10-18
PCT/US2000/028832 WO2001028557A1 (fr) 1999-10-18 2000-10-18 Derives indoliques cannabimimetiques

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EP1223929A4 EP1223929A4 (fr) 2002-12-04
EP1223929B1 true EP1223929B1 (fr) 2006-08-23

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EP (1) EP1223929B1 (fr)
JP (1) JP2003512326A (fr)
AU (1) AU1095101A (fr)
CA (1) CA2387138A1 (fr)
DE (1) DE60030303T2 (fr)
MX (1) MXPA02005101A (fr)
WO (1) WO2001028557A1 (fr)
ZA (1) ZA200203911B (fr)

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010009965A1 (en) 1998-05-04 2001-07-26 Alexandros Makriyannis Novel analgesic and immunomodulatory cannabinoids
US6943266B1 (en) 1999-10-18 2005-09-13 University Of Connecticut Bicyclic cannabinoid agonists for the cannabinoid receptor
AU778159B2 (en) 1999-10-18 2004-11-18 University Of Connecticut, The Peripheral cannabinoid receptor (CB2) selective ligands
FR2816938B1 (fr) * 2000-11-22 2003-01-03 Sanofi Synthelabo Derives de 3-aroylindole, leur procede de preparation et les compositions pharmaceutiques en contenant
US7507767B2 (en) 2001-02-08 2009-03-24 Schering Corporation Cannabinoid receptor ligands
US7067539B2 (en) * 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
WO2003007887A2 (fr) 2001-07-20 2003-01-30 Merck & Co., Inc. Imidazoles substitues servant de modulateurs de recepteurs de cannabinoides
US7528165B2 (en) 2001-12-13 2009-05-05 National Health Research Institutes Indole compounds
US6933316B2 (en) 2001-12-13 2005-08-23 National Health Research Institutes Indole compounds
US7632955B2 (en) 2001-12-13 2009-12-15 National Health Research Institutes Indole compounds
WO2003061699A1 (fr) * 2001-12-27 2003-07-31 Japan Tobacco, Inc. Remedes pour affections allergiques
FR2839718B1 (fr) 2002-05-17 2004-06-25 Sanofi Synthelabo Derives d'indole, leur procede de preparation et les compositions pharmaceutiques en contenant
EP1532132B1 (fr) * 2002-07-29 2008-03-19 F.Hoffmann-La Roche Ag Nouveaux benzodioxoles
CA2494091C (fr) 2002-08-02 2011-02-01 Richard B. Toupence Derives furo [2,3-b| pyridine substitues
US7183313B2 (en) 2002-08-23 2007-02-27 University Of Connecticut Keto cannabinoids with therapeutic indications
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US7329658B2 (en) 2003-02-06 2008-02-12 Pfizer Inc Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
TW200505902A (en) 2003-03-20 2005-02-16 Schering Corp Cannabinoid receptor ligands
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
WO2006069196A1 (fr) 2004-12-21 2006-06-29 Abbott Laboratories 3-cycloalkylcarbonyl indoles utilises comme ligands des recepteurs cannabinoides
US7456289B2 (en) 2004-12-31 2008-11-25 National Health Research Institutes Anti-tumor compounds
US8492428B2 (en) 2005-09-20 2013-07-23 Mayo Foundation For Medical Education And Research Small-molecule botulinum toxin inhibitors
NZ570014A (en) 2006-02-03 2011-04-29 Bionomics Ltd Substituted benzofurans, benzothiophenes, benzoselenophenes and indoles and their use as tubulin polymerisation inhibitors
US8841334B2 (en) 2006-05-31 2014-09-23 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
WO2007140439A2 (fr) 2006-05-31 2007-12-06 Abbott Laboratories Nouveaux composés constituant des ligands de récepteurs cannabinoïdes et utilisations de ces composés
US7875640B2 (en) 2007-03-28 2011-01-25 Abbott Laboratories Compounds as cannabinoid receptor ligands
US7872033B2 (en) 2007-04-17 2011-01-18 Abbott Laboratories Compounds as cannabinoid receptor ligands
US8735434B2 (en) 2007-05-18 2014-05-27 Abbvie Inc. Compounds as cannabinoid receptor ligands
US7943653B2 (en) * 2007-08-13 2011-05-17 Janssen Pharmaceutica N.V. Substituted 5-vinylphenyl-1-phenyl-pyrazole cannabinoid modulators
US9193713B2 (en) 2007-10-12 2015-11-24 Abbvie Inc. Compounds as cannabinoid receptor ligands
IE20070928A1 (en) * 2007-12-21 2009-09-30 Giuliani Int Ltd Multi target ligands
US8846730B2 (en) 2008-09-08 2014-09-30 Abbvie Inc. Compounds as cannabinoid receptor ligands
CA2737199A1 (fr) 2008-09-16 2010-03-25 Abbott Laboratories Composes inedits utilisables en tant que ligands des recepteurs cannabinoides
PA8854001A1 (es) 2008-12-16 2010-07-27 Abbott Lab Compuestos novedosos como ligandos de receptores de canabinoides
EP4108665A1 (fr) * 2016-06-23 2022-12-28 F. Hoffmann-La Roche AG Dérivés de [1,2,3]triazolo[4,5-d]pyrimidine ayant une affinité pour le récepteur de cannabinoïde de type 2

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2665444B1 (fr) * 1990-08-06 1992-11-27 Sanofi Sa Derives d'amino-benzofuranne, benzothiophene ou indole, leur procede de preparation ainsi que les compositions les contenant.
FR2735774B1 (fr) * 1995-06-21 1997-09-12 Sanofi Sa Utilisation de composes agonistes du recepteur cb2 humain pour la preparation de medicaments immunomodulateurs, nouveaux composes agonistes du recepteur cb2 et les compositions pharmaceutiques les contenant
DE19706903A1 (de) * 1997-02-21 1998-08-27 Bayer Ag Verwendung von bekannten Agonisten des zentralen Cannabinoid-Rezeptors CB 1

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WO2001028557B1 (fr) 2001-06-07
MXPA02005101A (es) 2003-09-25
DE60030303T2 (de) 2007-10-11
JP2003512326A (ja) 2003-04-02
EP1223929A4 (fr) 2002-12-04
CA2387138A1 (fr) 2001-04-26
DE60030303D1 (de) 2006-10-05
AU1095101A (en) 2001-04-30
EP1223929A1 (fr) 2002-07-24
WO2001028557A1 (fr) 2001-04-26
ZA200203911B (en) 2003-08-25

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